1. The Molecular and Clinical Heterogeneity of FH
G.Kees Hovingh MD PhD
AMC, Amsterdam, the Netherlands

2. Disclaimer Dr. Kees Hovingh is consultant and speaker for biotech
as well as pharmaceutical companies that develop
molecules that influence lipoprotein metabolism, including Regeneron, Pfizer, MSD, Sanofi, Amgen, Roche and Genzyme
Kees Hovingh is head of the Clinical Trial Unit of the department of Vascular Medicine at the AMC, Amsterdam, and
PI for clinical trials in dyslipidemia conducted with i.e.
Amgen, Sanofi, Lilly, Novartis, Kowa, Genzyme, Cerenis, Pfizer, Astra.
The department receives the honoraria and investigator fees.

3. FH, the traditional picture...

4. The same genotype may lead to extremely different phenotypes

5. And people might look alike while not sharing the genotype..8

6. FH diagnosis Clinical diagnosis Simon Broome Dutch Lipid Criteria
clinical +, mutation -
Simon Broome
Dutch Lipid Criteria
Clinical diagnosis
Molecular diagnosis
clinical -, mutation +

7. FH; “one disease?” EAS-consensus Clinical diagnosis
patient: treat LDL-C
family: “monitor LDL-C”
clinical +, mutation -
patient: treat LDL-C
family: mutation test
consider to treat LDLC
Clinical diagnosis
clinical +, mutation +
Molecular diagnosis
EAS-consensus
patient: monitor LDL-C
family: monitor LDL-C
clinical -, mutation +
Intervention is based on LDL-C, not on genetic result
Nordestgaard B et al Eur H J 2013;34:3478

8. Range of LDL-C in heFH?
Besseling, Hovingh, work in progress

9. HoADH in the Netherlands+
2 null alleles
No compound heterozygous or homozygous patients for PCSK9 mutations were detected.
Rural area…
1 null allele, 1 defective
2 defective alleles

10. HoADH in the Netherlands
No compound heterozygous or homozygous patients for PCSK9 mutations were detected.
Rural area…

11. Clinical Heterogeneity in daily life, outpatient clinic setting august 2015....

12. Clinical Heterogeneity in daily life, outpatient clinic setting august 2015....
referal letter:
“DC, please analyze CVD risk in mother of 9 year old boy with FH my outpatient clinic, best Bert Wiegman
(BTW; I ordered lab for her, she’ll bring it)”

13. LDL-C 9mmol/L
AMI age 51
LDL-C 3 mmol/L
LDL-C 6.5 mmol/L

14. Genetic analysis would help in this family
LDL-C 9mmol/L
AMI age 51
APOB truncation??
LDL-C 3 mmol/L
Genetic analysis would help in this family
LDL-C 6.5 mmol/L

15. FH; a matter of selection bias?
LDL-C 9mmol/L
AMI age 51
LDL-C 6 mmol/L
LDL-C 3 mmol/L

16. Is the FH phenotype (LDL-C and CVD) attenuated with increasing distance-to- index?

17. NO mutation: cascade stops in this branch
Data - collection
FH screening program in the Netherlands (‘94 - ‘14)
Genetic cascade approach
Questionnaire and blood sample (lipids since ‘04)
Index Subject for FH
1) Medical information
2) DNA Analysis
NO mutation: cascade stops in this branch
Mutation +
approach 1st
degree relatives
etc

19. Degrees of distance-to-index
Study population
Degrees of distance-to-index 1 2 3 4 5 6
No. (%)
7,512 (41.9%)
3,887 (21.7%)
1,493 (8.3%)
456 (2.5%)
38 (0.2%)
3 (0%)
Men *
3,568 (47.5%)
1,866 (48%)
735 (49.2%)
232 (50.9%)
22 (57.9%)
1 (33.3%)
Age in age †
40.9 (20.5)
33.1 (21.6)
26 (17.1)
17 (13,0)
16.7 (9.7)
8.9 (2.6)
Year of screening §
2006
[ ]
2007
[ ]
2009
[ ]
2008
[ ]
2001
[ ]
Body mass index in kg/m2 †
23.8 (5)
22.6 (5.3)
21.8 (5.2)
19.6 (4.8)
20.1 (5.4)
18.7 (5.7)
Smokers
1,969 (26.2%)
920 (23.7%)
306 (20.5%)
56 (12.3%)
9 (23.7%)
0 (0%)
Alcohol use
3,388 (45.1%)
1,633 (42%)
566 (37.9%)
100 (21.9%)
17 (44.7%)
CVD in medical history *‡
759 (10.1%)
285 (7.3%)
36 (2.4%)
1 (0.2%)
Hypertension *
812 (10.8%)
304 (7.8%)
54 (3.6%)
8 (1.8%)
* no. (%); † mean (SE); ‡ Defined as MI, CABG, PTCA, CVA or angina; § median [IQR]

20. Description heterozygous FH
Degrees of distance-to-index 1 2 3 4 5 6
Diabetes *
223 (3%)
84 (2.2%)
21 (1.4%)
1 (0.2%)
0 (0%)
Statin user *
2,997 (39.9%)
1,050 (27%)
265 (17.7%)
31 (6.8%)
User of
other LLT *
802 (10.7%)
240 (6.2%)
57 (3.8%)
9 (2%)
Lipid profiles (mg/dL)
LDL-C †
211 (80)
199 (75)
189 (72)
177 (65)
190 (77)
168 (152)
HDL-C †
46 (14)
46 (38,67)
53 (0.32)
41 (16)
Triglycerides § 99
[ ] 95
[ ] 92
[ ] 88
[ ] 90
[ ]
134
[ ]
* no. (%); † mean (SE); § median [IQR]
LLT: lipid lowering therapy

21. heFH; clinical diverse

22. CVD incidence in heterozygous FH

23. Does genetics matter?
Huijgen, Eur H J (18):

24. Does genetics matter?
No !!!

25. Another benefit of genetic analysis in FH
The new PCSK9??
if we do not sequence; we will not get to this!
clinical +, mutation -
Clinical diagnosis
Molecular diagnosis
clinical -, mutation +

26. “with every success it gets harder to find the next one”
???
PCSK9
APOB
LDLR
“with every success it gets harder to find the next one”

27. Conclusion 1) FH; a diverse disease: LDL-C is the driver, not genetics
2) No “devaluation” of phenotype in families: CVD risk and LDL-C
3) Genetics do help!
4) without molecular biology: no novel insights!